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Tiny fruit flies as powerful diabetes model

Tiny fruit flies as powerful diabetes model

Seung Kim

Fruit flies in your kitchen are unquestionably annoying. But the next time you’re trying to bat one out of the air around your too-ripe apples and bananas (or maybe that’s just me?), spare a few seconds to realize how important the tiny insects have been to science. They’ve been a darling of developmental biology for decades, as researchers identified genes (subsequently shown to be shared in mammals and humans) critically important in the metamorphosis from egg to animal. Frankly, it’s hard to over-estimate their contribution to science.

Now they’re set to take up a starring role in diabetes research. Stanford developmental biologist and Howard Hughes Medical Institute investigator Seung Kim, MD, PhD, and research associate Sangbin Park, PhD, have devised a way to measure insulin levels in fruit flies at the picomolar level – the level at which insulin concentrations are measured in humans. They’ve done so by successfully tagging the fruit fly insulin-like-peptide 2, or Ilp2, with a chemical tag. Their research was published today in PLOS Genetics.

From our release:

The experimental model is likely to transform the field of diabetes research by bringing the staggering power of fruit fly genetics, honed over 100 years of research, to bear on the devastating condition that affects millions of Americans. Until now, scientists wishing to study the effect of specific mutations on insulin had to rely on the laborious, lengthy and expensive genetic engineering of laboratory mice or other mammals.

In contrast, tiny, short-lived fruit flies can be bred in dizzying combinations by the tens of thousands in just days or weeks in small flasks on a laboratory bench.

In 2002, Kim and developmental biologist Roel Nusse, PhD, surprised many researchers when they showed that fruit flies develop a diabetes-like condition when their insulin-producing cells are destroyed. Further research has been stymied, however, by the difficulty of accurately measuring circulating insulin levels in the tiny animals. When speaking to me about the research, Kim called the new technique a “breakthrough” in the field.

Unlike many previous attempts by many groups, Park found two places in Ilp2 where the tag can be placed without affecting its biological activity. This allowed Kim and Park to track Ilp2 through its life cycle, as it’s produced by neurons in the brain (this is different from humans, who make insulin in beta cells in the pancreas), secreted into the blood stream and binds to insulin receptors in cells throughout the body. Parsing the effect of each mutation on the way the body produces, secretes and responds (or not) to insulin is critical to further understand the disease and to devise new therapeutic approaches. More from our release:

Park and his colleagues then turned their attention to mutations associated with type-2 diabetes in genome-wide studies in humans. These studies don’t reveal how a specific mutation might work to affect development of a disease; they show only that people with the condition are more likely than those without it to have certain mutations in their genome. Hundreds of candidate-susceptibility genes have been identified in this way.

Park and Kim used the technique to test in flies the molecular effects of human mutations known to be involved in the development of type 2 diabetes. They found that, when the mechanism of a human mutation was known, that mechanism worked similarly in flies. “I was stunned that this technique worked so well to identify the effect of specific mutations,” said Park. “Many of the genes we studied seem to have similar functions in governing insulin production or secretion in flies and in humans.”

Even more exciting, they were able to learn how some human mutations with previously unknown mechanisms actually worked. One, in a protein called BCL11A, was known to be associated with the development of the disease in humans, but its mechanism of action was unclear. Park and his colleagues found that blocking the expression of the fly version of BCL11A did not affect the flies’ ability to make Ilp2, but caused it to secrete abnormally high levels of Ilp2 into the bloodstream. As I wrote in the release:

The researchers emphasize that these findings are just the tip of the iceberg. Many more mutations can be studied alone and in combination under a myriad of experimental conditions. A single fruit fly can lay several hundred eggs during its approximately 40-day life span; eggs develop into adults in only 10 days. They plan to continue to use the fruit fly system to complement and inform their ongoing studies in mammals and humans.

Previously: Beta cell development explored by Stanford researchers and Stanford researchers identify new pathway governing growth of insulin-producing cells
Photo of Seung Kim by Steve Fisch

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